Cholagogic composition containing pentanedione derivatives

ABSTRACT

Cholagogic composition containing as active ingredients compounds of the formula:   WHEREIN R is a hydrogen atom or a lower alkyl group and n is an integer of 1 to 3, and a pharmaceutical carrier therefor.

ited States Patent Iloltotani et al.

CIIOLAGOGIC COMPOSITION CONTAINING PENTANEDIONE DERIVATIVES l Inventors: Hajime Yokotani, Osaka; Masuo Miyamoto, Kyoto; Tadakazu Murata, Osaka, all of Japan Assignee: Takeda Chemical Industries, Ltd.,

Osaka, Japan Filed: Sept. 28, 1972 Appl. No.: 293,169

Related US. Application Data Division of Ser. No, 56,971, July 21, 1970, Pat. No. 3,708,540.

Foreign Application Priority Data July 21, 1969 Japan 44-57562 US. Cl. 424/331 Int. Ul A6lk 27/00 Field of Search 424/331 Dec. 24, I974 Primary Examiner-Albert T. Meyers Assistant ExaminerDaren M. Stephens Attorney, Agent, or FirmWenderoth, Lind & Ponack [57] ABSTRACT Cholagogic composition containing as active ingredients compounds of the formula:

C O CH:

CI-Iz CH 00cm (0H),.

wherein R is a hydrogen atom or a lower alkyl group and n is an integer of 1 to 3, and a pharmaceutical carrier therefor.

3 Claims, N0 Drawings CHOLAGOGIC COMPOSITION CONTAINING PENTANEDIONE DERIVATIVES This is a division of application Ser. No. 56,971, filed From the reaction mixture thus obtained, the desired 3-benzyl-2, 4-pentanedione derivatives may be isolated in conventional manner such as recrystallization, distillation and chromatography.

July 21, 1970, now US. Pat. No. 3,708,540. 5 The starting material represented by the formula (11) This invention relates to novel 3-benzyl-2,4- is prepared, for example, by reacting a compound reppentanedione derivatives which are useful as cholaresented by the general formula gogue agents and to the production thereof. More specifically, this invention relates to novel 3-benzyl-2,4- pentanedione derivatives having the general formula (1) 1 COCH wherein R and n have the same meaning as above with CHI'CH acetylacetone in the presence of an organic base such coon; as pyridine and piperidine. (0K) (1) Pharmaceutical compositions containing one or more of the compounds of this invention can be prel R a hydrogen atom a lower alkyl group pared according to any per se conventional means for f h e l oi v er zil k fi g i lip ieiresented by R in the for Fhe Preparation Oftablet powder Capsule liquid or injection. mula exemphfied y alkyl havmg one five The compounds of this invention have an effective atoms Such as methyl, ethyl, -p pyh gp py cholagogic activity and are generally administered y i lsobutyli y i y i y y i orally in a formof tablet, powder, capsule, liquid, etc., etc., Where )1 stands for 2 and 3, R may be the same 01' o way of n eC[ n dlfferent- A typical effective dose of the compounds of this in- The Povlcompoundfi are Produced formstance, vention, when administered orally to human adult, is y sublectmg a Compound represented y the formula usually about 0. lg to 5.0g a day, desirably 0.3g to 1.5g. a a day and when administered intravenously, is usually about 0.5g. to 3.0g. per dose. Of course, an increased COCK or reduced dose is also effective or symptoms. -CH=O The physiological activity of the compounds of this I 00011, invention is demonstrated in the following tests. (011).. (11

wherein R and n have the same meaning as above, to T st for cholagogic activity hydrogenation. Each sample compound suspended with 5% gumm As the hydrogenation process applicable to this inarabic in physiological saline was administered orally to vention there may be employed per 58 known prorats (female, SD-JCL rat, weighing 200 10g, which cesses, for example, catalytic hydrogenation or hydrowas pentobarbital anesthetized after 20 hours fast) at genation with ainc and acetic acid, with stannouschlothe dosage of 100 mg./kg. The bile was continuously e Or with dlbOrane, and a g them, ytic hycollected through a polyethylene cannula inserted mto drogenation at ordinally atmospheric or superthe common bile duct and its volume was measured acatmospheric pressure is particularly advantageous for cording to the method described in H. Yokotani; Folia an industrial production. The catalyst for use in such a Pharmacologica Japonica 56, 1373-1386 1960). hydrogenation process may, for example, be a plati- The results are shown in Table 1. num, palladium, sodium or nickel catalyst, among them Samples: palladium-carbon catalyst is most desirable. Usually, 1. 3-(3'-methoxy-4'-hydroxybenzyl)-2.4- the catalytic hydrogenation reaction proceeds rapidly pentaedione at room temperature in a suitable solvent, which may, 2. 3-(4-hydroxybenzyl)-2,4-pentanedione for example, be any of alcohols such as methanol, etha- 3. l-phenylpropanol (produced and sold by Schering nol, etc., ethers such as ethyl ether, dioxane, etc., hy- Corp. under the tradename Felicur) drocarbons such as benzene, cyclohexane, etc., esters 4. p-hydroxyphenyl-salicylamide (produced by Yosuch as ethyl acetate etc., carboxylic acid such as acetic shitomi Pharmaceutical Co. Ltd. and sold by acid etc. and the like. These solvents may be used in Takeda Chemical 1nd. Ltd. under the tradename any combination or as a mixed solvent with water. Yoshichol) Table 1 Bile outflow (m1) Compound Number CI Bo of rats (0-1 hr.) 1-5 hr.) B value Evalualion 1 1) 4 0.94 4.04 103 (2) 4 1.00 4.41 1.21 None 16 1.10 3.50 0

(control) Table lContinued Bile outflow (ml) Compound Number C Bo of rats (-l hr.) (l-S hr.) B value Evaluation B= Bo h,C

Bo Total outflow during 4 hours after the administration of test compounds b, Ratio of bile outflow (bile volume in lhours/bile volume in 0-] hour in the control rats) C Bile outflow during 1 hour before the administration of compounds. :remarkably effective B E 1.0

++ fairly effective 1.0 820.7

:effective 0.7 B; 0.4 i slightly effective 0.4 B; 0.3 azl i fssttts..- B

Test for acute toxicity EXAMPLE 2 Each com oun sus nde with 57 um p d pe d I g m arable m in 200 parts by volume of methanol 15 added 7 parts physiological saline was adminishtered orally to mice (female ICR-JCL mouse, 4 weeks in age, weighing 18 r 2g.) Thus administered mice were observed for 4 days to estimate LD value. The results are shown in Table 2.

stand for kilogram(s)," gram(s) and milligram(s), respectively.

The present invention is further explained by way of the following illustrative examples.

In the following Examples, the relationship between part(s) by weight and part(s) by volume is the same as that between gram(s) and milliliter(s).

EXAMPLE 1 In 100 parts by volume of methanol is added 4.5 parts by weight of 3-(4-hydroxybenzylidene)-2,4- pentanedione. Under using 0.3 part by weight of palladiumcarbon as catalyst, the above mixture is subjected to catalytic hydrogenation at room temeperature (23 C) and under atmospheric pressure. After 1 hour, the reaction is complete with absorption of 540 parts by volume of hydrogen. The catalyst is filtered off, followed by washing with 80 parts by volume of methanol. The washing is combined with the filtrate. The solvent is distilled off, whereby 4.5 parts by weight of yellowish oily substance is obtained. 10 Parts by volume of benzene is added to the oily substance, and the mixture is stirred, whereby 3.6 parts by weight of 3-(4'- hydroxybenzyl)-2,4-pentanedione is obtained as crystals. The crystals are recrystallized from hot benzene to give faintly yellowish platy crystals melting at 90-9 1C.

Elementary analysis:

Calculated for C u n C 69.98 H 6.84 Found: C 70.09 H 6.93

by weight of 3-(3'-methoxy-4-hydroxybenzylidene)- 2,4-pentanedione. Using 0.5 part by weight of palladium-carbon (5%), the mixture is subjected to catalytic hydrogenation under the same conditions as in Example 1. After 80 minutes, the reaction is complete with absorption of 770 parts by volume of hydrogen. The reaction mixture is filtered, and the filtrate is concentrated. To the residue is added a small amount of ethyl acetate, and the mixture is kept standing, whereby colorless crystals of 3-(3'-methoxy-4-hydroxybenzyl)- 2,4-pentanedione and obtained. After separating the crystals by filtration, the crystals are washed with 4 parts by weight of ethyl acetate. The washing is combined with the filtrate, and the mixture is concentrated. whereby additional 0.6 part by weight of crystals are obtained. Recrystallization from aqueous alcohol gives colorless platy crystals melting at 75. C.

Elementary analysis:

lil lli l C 66.08 C 66.]?

Calculated for.

H 6.8.1 Found H 7.00

EXAMPLE 3 Elementary analysis:

Calculated for; C, -,H .,O;,

C 70.89 H 7.32 Found; C 70.3l H 7.32

EXAMPLE 4 in parts by volume of methanol is added 3 parts by weight of 3-(3', 4',5-trimethoxybenzylidene)-2,4- pentanedione, and then the mixture is subjected to eat- Elementary analysis: Calculated for; C H- tl 64.27 H 7.19 Found; c 64.16 H 7.03

EXAMPLE 5 In a mixture of 50 parts by volume of acetic acid and 30 parts by volume of ethyl acetate is dissolved parts by weight of 3-(3'-methoxy-4'-hydroxybenzylidene)- 2,4-pentanedione under heating. To the mixture, 6 parts by weight of zinc dust is added with stirring little by little in 20 minutes at room temperature. The resultant is subjected to filtration, and the residue is washed with 30 parts by volume of ethyl acetate. The washing is combined with the filtrate. The solvent is distilled off to leave 10 parts by weight of yellowish oily substance. The yellowish oily substance is subjected to column chromatography on silica gel (50 parts by weight) with a mixture of benzene and acetone (30:1) as an eluent. The fraction corresponding to the desired 3-(3- methoxy-4'-hydroxybenzyl)-2,4-pentanedione is collected, and the solvent is distilled off, whereby 6 parts by weight of colorless oily substance is obtained. The substance is crystallized from aqueous ethanol to obtain colorless crystals melting at 75C. A mixed melting of thus obtained product with the product of Example 2 does not show lowering of the melting point.

EXAMPLE 6 In 100 parts by volume of a mixture of ethyl acetate and methanol (1:1) is added 5 parts by weight of 3-(2- hydroxybenzylidene)-2,4-pentanedione. The mixture is subjected to catalytic hydrogenation at 24 C under atmospheric pressure by using platinum oxide. The reaction is finished in 1 hour. The catalyst is filtered off, and the solvent is distilled off from the filtrate, whereby 5 parts by weight of yellowish oily substance is obtained. The oily substance is subjected to column chromatog raphy on silica gel (80 parts by weight) with a mixture of benzene and ethyl acetate (20:1) as an eluent to obtain 3.0 parts by weight of 3-(2'-hydroxybenzyl)-2,4 pentanedione as pale yellowish oil boiling at l6ll 62 C(0.7mmHg).

Elementary analysis:

Calculated for: m u a C 69.88 H 6.84 n c 69.43 H 6.86

As indicated hereinbefore. the compounds of this invention can be administered in a variety of composition forms, some examples of which are as follows:

Composition 2.

mg. per tablet l Compound (2) 250 2) lactose 280 3) corn starch 4) magnesium stearate 65 Composition 3.

per ampoule 400 mg 6 ml 10 ml l Compound (I 2) propylene glycol 3) Sterile water. sufficient to make What is claimed is:

1. A method of administering to a human in need of a cholagogic agent an effective cholagogic amount of a composition consisting essentially of. as the active ingredient, a compound of the formula:

cocn

(OR) n wherein R is a hydrogen atom or a lower alkyl group and n is an integer of l to 3. and a pharmaceutical carrier therefor.

2. A method according to claim 1 wherein the active compound is 3-(3-methoxy-4-hydroxybenzyl)-2.4- pentanedione.

3. A method according to claim 1 wherein the active compound is 3-(4'-hydroxybenzyl)-2.4-pentanedione. 

1. A METHOD OF ADMINISTERING TO A HUMAN IN NEED OF A CHOLAGOGIC AGENT AN EFFECTIVE CHOLAGOGIC AMOUNT OF A COMPOSITION CONSISTING ESSENTIALLY OF, AS THE ACTIVE INGREDIENT, A COMPOUND OF THE FORMULA:
 2. A method according to claim 1 wherein the active compound is 3-(3''-methoxy-4''-hydroxybenzyl)-2,4-pentanedione.
 3. A method according to claim 1 wherein the active compound is 3-(4''-hydroxybenzyl)-2,4-pentanedione. 